ClinVar Miner

Submissions for variant NM_172201.1(KCNE2):c.161T>C (p.Met54Thr) (rs74315447)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148518 SCV000190230 likely pathogenic Cardiac arrhythmia 2014-06-01 no assertion criteria provided research
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058360 SCV000089880 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10219239;PMID:10984545;PMID:14760488;PMID:19716085;PMID:20042375;PMID:22378279). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000212497 SCV000223517 uncertain significance not provided 2018-09-04 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the KCNE2 gene. The M54T variant has been reported multiple times in individuals with various phenotypes including arrhythmia, sudden death, and drug-induced arrhythimia, and in individuals referred for LQTS genetic testing (Abbott et al., 1999; Sesti et al., 2000; Kapplinger et al., 2009; Tester et al., 2012; Nawathe at el., 2013; Wang et al., 2014). The M54T variant is observed in 53/10152 (0.5%) alleles from individuals of Ashkenazi Jewish ancestry, indicating it may be a rare benign variant in this population, and in 9/126710 (0.007%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). Nevertheless, the M54T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Multiple functional studies demonstrate that M54T has a significant effect on potassium ion channel function in the heart (Abbott et al., 1999; Lu et al., 2003; McCrossan et al., 2009; Wu et al., 2010). Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000006425 SCV000839965 risk factor Long QT syndrome 6 2018-03-17 criteria provided, single submitter clinical testing This c.161T>C (p.Met54Thr) variant in the KCNE2 gene has been reported in patients with variable presentations such as arrythmias, sinus bradycardia and long QT syndrome [PMID 10219239, 19716085, 23631727]. This variant was first reported in a patient with atypical response to exercise with prolonged QTc intervals [PMID 10219239]. In vitro functional assays showed that the variant affect protein function [PMID 23631727, 20042375, 24569893]. This variant has been detected in 29 heterozygous individuals from Europe in the ExAC population database (http://exac.broadinstitute.org/variant/21-35742938-T-C). Methionine at amino acid position 54 of the KCNE2 protein is highly conserved in mammals. While not validated for clinical use, computer-based algorithms SIFT and Polyphen-2 predict this p.Met54Thr change to be deleterious. This variant is thus classified as a risk factor.
Illumina Clinical Services Laboratory,Illumina RCV000407848 SCV000435623 likely pathogenic KCNE2-Related Disorders 2017-04-28 criteria provided, single submitter clinical testing The KCNE2 c.161T>C (p.Met54Thr) variant has been reported in at least four studies in individuals with long QT syndrome (LQTS), drug-induced LQTS, or sudden unexplained death (SUD), and is found in a heterozygous state in six individuals (Abbot et al. 1999; Sesti et al. 2000; Kapplinger et al. 2009; Wang et al. 2014). The p.Met54Thr variant was also identified in two of over 6100 presumed healthy individuals (Freudenberg-Hua et al. 2014; Ghouse et al. 2015). The p.Met54Thr variant was absent from over 2300 controls and is reported at a frequency of 0.00043 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies indicated that the p.Met54Thr variant causes a reduction in current density in the potassium ion channel (Abbot et al. 1999; Sesti et al. 2000; Wu et al. 2010). Based on the collective evidence, the p.Met54Thr variant is classified as likely pathogenic for KCNE2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000006425 SCV000770223 benign Long QT syndrome 6 2017-10-27 criteria provided, single submitter clinical testing
OMIM RCV000006425 SCV000026608 pathogenic Long QT syndrome 6 1999-04-16 no assertion criteria provided literature only

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